1. Field of the Invention
This invention relates to a carcinostatic for a hormonotherapy containing dienogest or its solvate as an effective component, a therapeutic agent for a sex hormone-dependent cancer containing dienogest or its solvate as an effective component, or a therapeutic agent for uterine cancer and/or breast cancer, which contains dienogest or its solvate as an effective component.
2. The State of the Art
Dienogest is the International Nonproprietary Names (INN) of a known compound, (17.alpha.-cyanomethyl-17.beta.-hydroxyestra-4,9(10)-dien-3-one) having a structure represented by formula (I): ##STR2##
The nature and synthesis of this compound are compactly described in Schubert et al., Elsevier Science Publishers ed., Natural Products Chemistry, 1984, 143-158.
Dienogest is known to have progestational activity, and in Germany, a combined drug of dienogest with ethynylestradiol is recently purchased as an oral contraceptive. Use of the dienogest as a therapeutic agent for endometriosis has also been attempted (Exp. Clin. Endocrinol. 94, 1-2, 211, 1989). However, there has so far been no report indicating the carcinostatic activity of the dienogest.
It has also been reported that dienogest is free from androgenic activity, which is different from other compounds with progestational activity (Schubert et al., Elsevier Science Publishers ed., Natural Products Chemistry, 1984, 143-158, supra).
One current research theme in the field of cancer and hormone is "hormone dependency of cancer", and various researches are made on the influence of biological hormones on the initiation, promotion and progression of cancer. In view of such researches, hormonotherapy has become an important pharmacotherapy in treating typical sex hormone-dependent cancers such as uterine (endometrial carcinoma) cancer, breast cancer, prostate cancer, and thyroid gland cancer.
For example, more than 95% of uterine cancer are adenocarcinoma, and the cells in the uterine cancer lesion often retain some of the characteristics of epitherial cells of the endometrium in its proliferative phase. Such cells are believed to proliferate in the absence of progesterone by the stimulation of estrogen (Gurpide, J. Natl. Cancer Inst., 83, 6, 405-416, 1991). In view of such reports, hormonotherapies utilizing antiestrogens or progestins have been attempted as a pharmacotherapy in addition to conventional chemotherapies for the uterine cancer.
Antiestrogens such as tamoxifen and its derivatives have been attempted for use in such hormonotherapy. With regard to such antiestrogens, it has been reported that tamoxifen or its derivatives rather promoted the growth of uterine cancer cell lines, and that a long-term administration of tamoxifen as an adjuvant to which chemotherapy of breast cancer resulted in an increased risk of the uterine cancer incidence. Moreover, sensitivity of the uterine cancer cells to antiestrogens is not uniform, so that therapeutic effectivity of the use of an antiestrogen for the uterine cancer is not yet confirmed. (Gurpide, J. Natl. Cancer Inst., 83, 6, 405-416, 1991, supra.)
With regard to the progestins, use of orally administrable 17.alpha.-hydroxyprogesterone, megestrol, medrogestone, and medroxyprogesterone in hormonotherapy has been attempted. Among these, medroxyprogesterone has been found to have therapeutic effects for the uterine cancer when it is administered at a high daily dose of from 400 to 600 mg (Kurihara et al., Sanfujinka-no Jissai (Obstetrical and Gynecological Practice), 34, 517-536, 1985), and a high dose preparation of medroxyprogesterone has been developed and purchased.
However, even when the medroxyprogesterone is administered at such a high dose, the percentage of successful therapy is still 23.6% (Kurihara et al., Sanfujinka-no Jissai (Obstetrical and Gynecological Practice), 34, 517-536, 1985, supra), while side effects of the medroxyprogesterone, which are believed to be caused by corticoid activity or androgenic activity of the medroxyprogesterone, become notable. Accordingly, the medroxyprogesterone can inevitably be used with caution (Okada et al., Sanfujinka-no Jissai (Obstetrical and Gynecological Practice), 38, 4, 575-582, 1989).
Almost all breast cancer and prostate cancer are believed to be caused under the actions of estrogen and androgen. Hormonotherapies using antiestrogens or progestins are also attempted in the treatment of the breast cancer as a pharmacotherapy, as in the case of the above-described uterine cancer. Typical antiestrogens are tamoxifen and its derivatives. However, these antiestrogens are not necessarily optimal since induce from side effects including blood disorders such as leukopenia and hypercalcemia as well as an increased risk of the uterine cancer incidence after a long-term administration as mentioned above. Typical progestin is the above-described medroxyprogesterone. However, as in the case of uterine cancer, medroxyprogesterone has to be administered at a high dose, i.e. at a daily dose of from 600 to 1,200 mg, and the above-mentioned side effects, which are believed to be caused by the corticoid activity or the androgenic activity of the medroxyprogesterone, become notable.
In the treatment of prostate cancer, therapies using the progestins has been attempted in addition to the therapies using estrogens.
Recently, cases have been reported wherein serious thrombosis in brain, heart, lung and the like have been induced as side effects of a high dose administration of medroxyprogesterone in treating sex hormone-dependent cancers, in particular, uterine cancer and breast cancer. In view of such situation, Safety Division of the Pharmaceutical Affairs Bureau, Japanese Ministry of Health and Welfare has called for an attention to the development of thrombosis in the use of medroxyprogesterone (Iyakuhin Kenkyu (Researches on Pharmaceuticals), 23, 5, 664-671, 1992).
As described above, the sufficient effective percentage of successful therapy in the hormonotherapy for sex hormone-dependent cancer is not still achieved, and such hormonotherapy is accompanied with serious side effects. In improving the therapeutic effects as well as the safety of such hormonotherapy in the sex hormone-dependent cancers, it is a matter of urgency to develop a drug that has a novel pharmacological activity and exhibits a broader range of therapeutic effects including the effects for the sex hormone-dependent cancers that had failed to respond to the conventional hormonotherapies. Such drug should also exert its therapeutic effects at a low dose, and has least side effects including thrombosis, cardiocoronary diseases, arteriosclerosis, Cushing's syndrome, and moon face, that are believed to be induced by the androgenic activity or the corticoid activity of the drug.